Extrinsic and intrinsic factors regulating commensal-specific T helper-17 cells

项目摘要 -- 现在人们普遍认识到，肠道共生细菌在健康和疾病中发挥着重要作用。而当 肠道菌群失调已被证明与许多自身免疫异常有关，尤其是 特定微生物种类和宿主免疫状态之间的关系仅为 少量的有机体。最近的研究支持这样一种观点，即分段丝状细菌 是一种关键的肠道共生细菌，可以驱动粘膜Th17反应，这可以说是最 这一领域的激动人心的发现。然而，在发展的关键方面存在着激烈的争论 粘膜Th17细胞。利用最近开发的独特工具，我们旨在解决三个重要的问题 问题：(1)哪些细胞因子是诱导SFB特异性Th17细胞所必需的；(2)哪些是特异性的 粘膜中呈现细菌抗原的APC亚群；以及(3)TCRs的抗原亲和力如何影响 Th17分化。这一建议的可行性得到了(1)我们开发的许多独特工具的支持， 包括CD4T细胞杂交瘤、新型TCR转基因小鼠和转基因单核细胞增多性李斯特菌；以及(2) 我们在黏膜免疫学，特别是这个实验系统方面的第一手经验。 从这个项目中得出的见解对于理解和利用粘膜免疫将是重要的。 回应。

Project Summary   It is now widely appreciated that gut commensal bacteria play a major role in health and disease. While dysregulation of the intestinal flora has been shown to contribute to many autoimmune abnormalities, specific relationships between particular microbial species and the state of host immunity have been unraveled for only a small number of organisms. Recent studies have supported the notion that segmented filamentous bacterium is a key gut commensal bacterium for driving mucosal Th17 responses, which is arguably one of the most exciting discoveries in the field. However, there exist intense debates on key aspects of the development of mucosal Th17 cells. Taking advantage of unique tools recently developed, we aim to address three important questions: (1) Which cytokines are required for SFB-specific Th17 cell induction; (2) What are the specific mucosal APC subsets that present bacterial antigens; and (3) How does antigen affinity of TCRs impact on Th17 differentiation. The feasibility of this proposal is supported by (1) many unique tools that we developed, including CD4 T cell hybridomas, novel TCR transgenic mice and transgenic Listeria monocytogenes; and (2) our first-hand experience in mucosal immunology in general and with this experimental system in particular. Insights to be derived from this project will be important for understanding and harnessing mucosal immune responses.